EP0880540B1 - 17-beta-cyclopropyl(amino/oxy) 4-aza steroides utilises en qualites d'inhibiteurs de 5-alpha-reductase et de c17-20-lyase de testosterone - Google Patents

17-beta-cyclopropyl(amino/oxy) 4-aza steroides utilises en qualites d'inhibiteurs de 5-alpha-reductase et de c17-20-lyase de testosterone Download PDF

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Publication number
EP0880540B1
EP0880540B1 EP97901995A EP97901995A EP0880540B1 EP 0880540 B1 EP0880540 B1 EP 0880540B1 EP 97901995 A EP97901995 A EP 97901995A EP 97901995 A EP97901995 A EP 97901995A EP 0880540 B1 EP0880540 B1 EP 0880540B1
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aza
androst
mmol
compound according
androstan
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EP0880540A1 (fr
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James R. Pribish
Cynthia A. Gates
Philipp M. Weintraub
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Aventis Pharmaceuticals Inc
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Aventis Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J73/00—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms
    • C07J73/001—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom
    • C07J73/005—Steroids in which the cyclopenta[a]hydrophenanthrene skeleton has been modified by substitution of one or two carbon atoms by hetero atoms by one hetero atom by nitrogen as hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the enzyme steroid C 17,20 lyase cleaves the 17-20 carbon-carbon bond in steroids having a two carbon side chain at the 17 ⁇ -carbon position to form important precursor molecules to the formation of testosterone, 5 ⁇ -dihydrotestosterone and the estrogens, principally estrone and estradiol.
  • Compounds which inhibit this enzyme would thus serve to inhibit the formation of the indicated precursors and thereby be useful in the treatment of various androgenic as well as estrogenic disorders.
  • a treatment incorporating such enzymatic inhibitors is not limited to the origin of the precursor molecule, such as various organ ablation techniques which are currently known. For example, while orchiectomy will effectively reduce gonadal androgen, it will have not have significant effect upon adrenal androgen production.
  • such an enzymatic treatment is a much more focused treatment in that it is directed to the immediate hormonal imbalance believed responsible for the condition, as opposed to a broad spectrum remedy which not only affects the particular symptom, but causes permanent endocrine defects necessitating life-long dependency on replacement therapy.
  • Prostatic cancer or neoplastic tissue disorders which originate in the parenchymal epithelium of the prostate is one of the most common malignancies among men, and exhibits one of the highest cancer-specific deaths of all malignant carcinomas. It is known that patients with metastatic prostate cancer respond positively to hormonal therapy. It is reported by Cookson and Sarosdy that androgen ablation has had a positive, beneficial response for as high as 60% to 80% for all patients tested. (Cookson C.S. and Sarosdy, M.F., South Med. J 87:1-6).
  • C 17,20 lyase inhibitors would be useful in the treatment of hormonal dependent prostatic carcinoma, prostatic hyperplasia, virilism, congenital adrenal hyperplasia due to 21-hydroxylase deficiency, hirsutism, hormonal dependent breast cancer, polycystic ovarian syndrome correlated with elevated C 17,20 lyase activity as well as other neoplastic tissue disorders such as endometrial, hepatocellular and adrenal carcinomas.
  • the enzyme steroid 5 ⁇ -reductase present in mammalian tissues including skin, male genitalia and the prostate, catalyzes the conversion of testosterone (17 ⁇ -hydroxy-androstan-4-en-3-one) into dihydrotestosterone or DHT (17 ⁇ -hydroxy-5 ⁇ -androst-3-one), which is also known as scanolone.
  • DHT is a more potent androgen than testosterone, and acts as an end-organ effecter in certain tissues, particularly in mediating growth. DHT formation can occur in certain tissues themselves by the action of 5 ⁇ -reductase.
  • androgen dependent disorders such as benign prostatic hyperplasia and prostatic cancer, including hormonal dependent carcinoma, the inhibition of DHT would be highly desirable.
  • the conversion of testosterone co DHT itself can be associated with various androgenic disorders, especially when DHT levels build up to excessive amounts.
  • DHT levels build up to excessive amounts.
  • high levels of DHT in the skin has been associated in the pathogenesis of acne, including acne vulgaris.
  • the enzyme C 17 -hydroxylase catalyzes the C 17 hydration of steroid substrates during the biosynthesis of cortisol.
  • C 17-20 lyase and C 17 -hydroxylase are different active sites of the same enzyme, the inhibition of one usually results in the disabling of the other.
  • Cortisol excess results in a syndrome characterized by hypokalemia, metabolic alkalosis, polydipsia, polyuria, Cushing's syndrome and hypertensive conditions. Inhibition of cortisol synthesis via C 17 ⁇ -hydroxylase would therefor have therapeutic effect for the treatment of these disorders or conditions.
  • the present invention relates to 4-aza-17-(cyclopropoxy)-androst-5a-androstan-3-one, 4-aza-17-(cyclopropylamino)-androst-4-en-3-one and related compounds and to compositions incorporating these compounds, as well as the use of these compounds in the treatment of conditions which would be affected by inhibition of C 17-20 lyase and/or 5 ⁇ -reductase, including androgen and estrogen mediated disorders, such as, for example benign prostatic hyperplasia, DHT-mediated disorders, such as, for example, acne, estrogen dependent breast cancer and androgen mediated prostatic cancer.
  • disorders which are characterized by an oversynthesis of cortisol can also be treated by the compounds of the invention.
  • hypokalemia for example, hypokalemia, metabolic alkalosis, polydipsia, polyuria, Cushing's syndrome and hypertensive conditions.
  • the compounds of the invention may be administered in combination with other effective treatment for enhanced therapeutic effect.
  • other effective treatment for enhanced therapeutic effect.
  • androgen-dependent disorders including prostatic cancer, flutamide, a known androgen receptor antagonist may be used in combination with the compounds of the invention.
  • the present invention is directed to a group of compounds, and to their pharmaceutically acceptable salts, having the following general formula: wherein:
  • C 1-4 alkyl means any straight or branched chain alkyl radical of one to four carbon atoms. For example, methyl, ethyl; n -propyl, isopropyl, n -butyl, sec -butyl, tert -butyl and the like.
  • C 2-4 alkenyl means any straight or branched chain alkene radical or two to four carbon atoms.
  • ethenyl vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1,3-butenyl and the like.
  • C 1-4 alkylthio, C 1-4 alkylsulfinyl or C 1-4 alkylsulfonyl means C 1-4 alkyl-Y-, where C 1-4 alkyL is as defined above, and Y is S, SO or SO 2 radical, respectively, and as depicted in Scheme G.
  • Ph-S-, Ph-SO- or Ph-SO 2 - is defined in a similar manner, or Ph-S-, Ph-SO- or Ph-SO 2 -.
  • C 1-4 alkanoyloxy defines a final product molecule which is the ester condensation product of the corresponding steroid alcohol with a straight or branched chain carboxylic acid of from one to four carbon atoms.
  • carboxylic acid of from one to four carbon atoms.
  • C 1-4 alkoxycarbonylmethyl means a C 1-4 alkyl, as defined above, ester of acetic acid, all of which form a substituent bonded at the ⁇ -carbonyl carbon to the steroid nucleus, as represented in Scheme K.
  • C 1-4 -alkoxycarbonyl means C 1-4 alkyl, as defined above, ester of formic acid, all of which forms a substituent bonded at the carbonyl carbon to the steroid nucleus, as represented in Scheme L.
  • C 1-4 alkanoyl means a ketone of from one to four carbon atoms, bonded to the steroid nucleus at the carbonyl carbon, as represented in Scheme M.
  • ethanoyl isopropanoyl, n -butanoyl, s -butanoyl, t -butanoyl.
  • halo means a chloro, bromo, fluoro or iodo substituent.
  • the term "pharmaceutically acceptable salt” is intended to mean any organic or inorganic acid salt which is capable of forming a non-toxic acid addition salt which is suitable for use as a pharmaceutical.
  • Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulphuric, and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate, and potassium hydrogen sulfate.
  • Illustrative organic acids which form suitable salts include the mono-, di- and tri-carboxylic acids.
  • suitable pharmaceutically-acceptable salts are recited in Berge, S.M. et al, J. Pharm Sci. 66:1, 1 (1977), which is herein incorporated by reference. Such salts can exist in either a hydrated or substantially anhydrous form.
  • the term "patient” refers to a warm blooded animal such as a mammal which is afflicted with a particular disease. It is explicitly understood that guinea pigs, dogs, cats, rats, mice, horses, cattle, sheep and humans are example of animals within the scope of the meaning of the term.
  • the term "effective inhibitory amount" is such an amount wherein an enzyme inhibitory effect is achieved sufficient to cause a therapeutic effect in the patient.
  • the exact amount of compound to be administered can be readily determined by the attending diagnostician, as one skilled in the art, by the use of conventional techniques and by observing results obtained under analogous circumstances. Factors significant in determining the dose include: the dose; the species of animal, its size, age and general health; the specific disease involved, the degree of or involvement or the severity of the disease; the response of the individual patient; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. That said, the exact amount employed may vary over a wide range. For example, from about 0.625 to 200 mg/kg of body weight per day, preferably from about 0.5 mg to 100 mg/kg of body weight per day.
  • the active ingredient is preferably incorporated into a composition containing a pharmaceutical carrier, although the compounds are effective, and can be administered, in and of themselves.
  • pharmaceutical carrier refers to known pharmaceutical excipients useful in formulating pharmaceutically active compounds for administration, and which are substantially nontoxic and nonsensitizing under conditions of use. The exact proportion of these excipients are determined by the solubility and chemical properties of the active compound, the chosen route of administration as well as standard pharmaceutical practice. That said, the proportion of active ingredient can vary from about 5% to about 90% by weight.
  • the pharmaceutical compositions of the invention are prepared in a manner well known in the pharmaceutical art.
  • the carrier or excipient may be a solid, semisolid, or liquid material which can serve as a vehicle or medium for the active ingredient. Suitable carriers or excipients are well known in the art.
  • the pharmaceutical composition may be adapted for oral, inhalation, parenteral, or topical use and may be administered to the patient in the form of tablets, capsules, aerosols, inhalants, suppositories, solution, suspensions, powders, syrups, and the like.
  • the term "pharmaceutical carrier” means one or more excipients.
  • effective routes of administration may include, subcutaneously, intramuscularly, intravenously, transdermally, intranasally, rectally and the like including release from implants as well as direct injection of the active ingredient and/or composition directly into the tissue or tumor sites.
  • suitable pharmaceutical carriers and formulation techniques are found in standard texts, such as Remington's Pharmaceutical Sciences , Mack Publishing Co., Easton Pennsylvania, which is herein incorporated by reference.
  • the compounds can be formulated into solid or liquid preparation, with or without inert diluents or edible carrier(s), such as capsules, pills, tablets, troches, powders, solutions, suspensions or emulsions.
  • the tablets, pills, capsules, troches and the like may also contain on or more of the following adjuvants: binders such as microcrystalline cellulose, gum tragacanth or gelatin; excipients such as starch or lactose, disintegrating agents such as alginic acid, Primogel®, corn starch and the like; lubricants such as stearic acid, magnesium stearate or Sterotex®, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; and flavoring agents such as peppermint, methyl salicylate or fruit flavoring,
  • a liquid carrier such as polyethylene glycol or a fatty oil. Materials used should be pharmaceutically pure and non-toxic in the
  • the compounds may be administered as injectable dosages or a solution or suspension of the compound in a physiologically acceptable diluent with a pharmaceutical carrier which can be a sterile liquid such as water-in-oil with or without the additions of a surfactant and other pharmaceutically acceptable excipients.
  • a pharmaceutical carrier which can be a sterile liquid such as water-in-oil with or without the additions of a surfactant and other pharmaceutically acceptable excipients.
  • oils which can be employed in the preparations are those or petroleum, animal, vegetable or synthetic origin.
  • peanut oil, soybean oil, and mineral oil for example, peanut oil, soybean oil, and mineral oil.
  • water, saline, aqueous dextrose and related sugar solutions, ethanols and glycols, such as propylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • the parental preparation can be enclosed in ampules, disposable syringes or multiple dose vials made of inert glass or plastic.
  • solutions or suspension described above may also include one or more of the following adjuvants; sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as ascorbic acid or sodium bisulfite; chelating agent such as ethylene diaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose.
  • sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents, antibacterial agents such as ascorbic acid or sodium bisulfite
  • chelating agent such as ethylene diaminetetraacetic acid
  • buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dex
  • the compounds can be administered in the form of a cutaneous patch, a depot injection, or implant preparation which can be formulated in such a manner as to permit a sustained release of the active ingredient.
  • the active ingredient can be compressed into pellets or small cylinders and implanted subcutaneously or intramuscularly as depot injections or implants.
  • Implants may employ inert materials such as biodegradable polymers and synthetic silicones. Further information on suitable pharmaceutical carriers and formulation techniques are found in standard texts such as Remington's Pharmaceutical Sciences.
  • Scheme A represents a potential syntheses for the C 17 -cyclopropyl-5-ene steroid compounds of the invention starting from testesterone.
  • Testosterone or 17 ⁇ -hydroxy-androst-5(6)-en-3-one [1] is treated with a strong oxidizer which breaks open the A-ring of the steroid nucleus to give the corresponding 4-nor-3,5- seco -acid [2].
  • a strong oxidizer which breaks open the A-ring of the steroid nucleus to give the corresponding 4-nor-3,5- seco -acid [2].
  • potassium permanganate with sodium periodate in aqueous potassium carbonate and tert-butanol or methanolic ozone in methylene chloride at reduced temperature have proved effective. Care should be taken, however, to assure that over-oxidation does not occur, thereby converting the C 17 -hydroxy substituent into a ketone.
  • the seco -acid [2] can be converted into the corresponding lactam or 4-aza steroid [3] by refluxing in the presence of an ammonium acid addition salt and an acid.
  • an ammonium acid addition salt and an acid for example, ammonium acetate in acetic acid.
  • the corresponding 4-alkyl-aza compounds of the invention can be prepared by refluxing with the appropriate alkylamine or alkylamine hydrochloride under acidic conditions.
  • the seco -acid [2] is refluxed with methylamine hydrochloride in the presence of acetic acid.
  • the acid addition ester [3] can be converted into the corresponding 17-alcohol [4] under basic hydrolysis conditions, such as aqueous sodium hydroxide in ethanol.
  • Tetrahydrofuran (THF) may be employed, as necessary to assist in the solubility of the steroid substrate.
  • the 17-alcohol [4] can be converted into the vinyl ether [5] by etherification with a vinyl ether in the presence of a suitable etherification catalyst and solvent.
  • a suitable etherification catalyst and solvent for example, ethyl vinyl ether and mercuric acetate in chloroform or chloroform/tert-butyl methyl ether.
  • the vinyl ether [5] can then be converted into the cyclopropyl ether [6] under typical cyclopropanation conditions, such as by reaction with tert-butyl methyl ether, diethyl zinc and methylene iodide in methylene chloride.
  • Scheme B graphically illustrates a synthetic route for the preparation of the saturated B-ring C 17 -cyclopropyl ether compounds of the invention.
  • the 5-ene C 17 -acid ester [3] is hydrogenated to the saturated acid ester [7] and then hydrolyzed to the saturated 17-alcohol [8].
  • Typical hydrogenation conditions include heating with hydrogen in the presence of ethanol and 5% palladium on carbon catalyst.
  • the hydrolysis conditions are similar to those reported under Scheme A, aqueous sodium hydroxide in ethanol and tetrahydrofuran, the solvent choice as necessary to dissolve the reactants.
  • the hydrogenation and hydrolysis steps may be reversed, that is, under Option B, the 5(6) unsaturated 17-alcohol [4] is created directly by hydrolyzing the acid ester [3], and then hydrogenated to give the saturated 17-alcohol [8].
  • the 17-alcohol [8] can then be etherified and cyclopropanated as described in Scheme A to give the 17 ⁇ -cyclopropylether [9].
  • inert substituent in the definition of R', it is meant a substituent(s) which is (are) unaffected by the reaction conditions of the scheme.
  • Scheme C illustrate a potential synthesis for the preparation of the compounds of the invention having a 17-cyclopropylamino substituent.
  • the starting compound, testosterone [1] is treated to oxidation conditions sufficient to break open the A-ring of the steroid nucleus to give the corresponding 17-keto-4-nor-3,5- seco -acid [10].
  • This may be effected in a manner similar to that described for the preparation of compound [2] in Scheme A.
  • modified reaction conditions from the Scheme A ring cleavage are employed. For example, bubbling ozone at reduced temperature (-78°C) in methylene chloride and ethyl acetate.
  • Non-alchoholic solvents are employed to ensure that transesterification with the newly formed seco-acid does not occur.
  • the seco-acid [10] is converted into the corresponding 17-keto lactam or 4-aza steroid [11] under the application of conditions similar to those described for the corresponding reaction in Scheme A. For example, refluxing in the presence of ammonium acetate and acetic acid.
  • the 4-alkyl compounds may be prepared in a similar manner, e.g., refluxing in acidic alkylamine or acidic alkylamine hydrochloride.
  • the 17-keto lactam [11] is converted into the corresponding 17-cyclopropylimino compound [12] by reaction with cyclopropylamine in chloroform.
  • THF may be used as a cosolvent, if necessary to solubilize the steroid substrate.
  • the cyclopropylimine [12] is reduced to the corresponding 17-cyclopropylamine [13] by reaction with a suitable reducing agent such as sodium borohydride.
  • the saturated cyclopropylamino compounds of the invention can be prepared also under Scheme C following Route B.
  • the 17-keto lactam [11] is hydrogenated preferentially by action of H 2 gas with palladium catalyst to obtain the saturated 17-hydroxy lactam [14].
  • the 17-alcohol [14] may be oxidized to the corresponding 17-ketone
  • Scheme D illustrates a potential synthesis for the 1-halo- ⁇ 1 compounds of the invention.
  • the synthesis may begin with the saturated acid ester [7], also an intermediate of Scheme B.
  • the acid ester [7] is dehydrogenated preferentially at the ⁇ 1(2) positions to give the corresponding 1(2)-ene [16], as is known.
  • reaction with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and bis(trimethylsilyl)-trifluoroacetamide (BSTFA) in dioxane. Bhattacharya et al. J. Am. Chem.
  • the hydrolysis, vinylation and cyclopropanation may be performed in a manner similar to that described under Scheme A to give the ⁇ 1(2) -ene-17-cyclopropylether [17].
  • the 17-cyclopropylamine [17] is formed by first hydrolysing to the 17-alcohol, as under option A, but then oxidizing, cycloaminating and reducing as described under Route B in Scheme C.
  • Compound [17] can be converted into the corresponding 1-phenylthioether [18] by reaction with phenylmercaptan (thiophenol) in sodium hydride.
  • the thioether [18] can be changed into the 1,2-dihalo compound [19] by reaction with N-bromo-succinimide (NBS) and diethylaminosulfur trifluoride (DAST).
  • NBS N-bromo-succinimide
  • DAST diethylaminosulfur trifluoride
  • the 2-halo substituent can then be eliminated by reaction with tributyltin hydride and azobisisobutyronitrile to give the desired 1-fluoro- ⁇ 1(2) compound [20].
  • This compound [20] may be hydrogenated, if desired by reaction with H 2 gas over palladium to give the saturated 1-fluoro compound [21].
  • Scheme E graphically represents a potential synthesis for the 1-phenylsulfinyl and 1-phenylsulfonyl compounds of the invention, starting from the 1-phenylthioether [18], the preparation thereof described in Scheme D, as is known.
  • compound [18] may be reacted with 3-chloroperoxybenzoic acid at reduced temperature (-78°C) for 3 hours under nitrogen to create the 1-phenylsulfinyl thioether.
  • the 1-phenylsulfonyl thioether is created under similar reaction conditions as the sulfinyl ether, except the reaction occurs at room temperature, and the time is extended to 16 hours.
  • Scheme F represents the preparation of the 2 ⁇ -halo compounds of the invention, starting from the 4-aza-17-alcohol [14], the preparation thereof is described in Scheme C, Route B.
  • the 17-alcohol [14] is first converted into the protected ether [24] by any effective means, for example by reaction with trimethylsilyl chloride in methylene chloride.
  • the protected ether [24] may then be halogenated by reaccion with N,N,N',N'-tetramethylethylenediamine (TMEDA) and the desired halogenated silyl agent at reduced temperature under an inert atmosphere. Once halogenated, the protecting group is removed for subsequent conversion of the 17-substituent.
  • TEDA N,N,N',N'-tetramethylethylenediamine
  • trimethylsilyliodide and bromine in TMEDA and toluene may be used initially, followed by tetrabutyl ammonium fluoride (TBAF) in tetrahydrofuran (THF).
  • TBAF tetrabutyl ammonium fluoride
  • THF tetrahydrofuran
  • the iodide [26] may be created by trimethylsilylchloride and iodine in TMEDA in toluene, followed by the action of TBAF in THF.
  • the 2 ⁇ -halogens [25]-[26] can then be converted into the corresponding 17 ⁇ -cyclopropylamino compound [27]-[28] as in Scheme C, or the corresponding 17 ⁇ -cyclopropyloxy compound [27]-[28] as described in Scheme A.
  • Scheme G represents a synthesis for the creation of the 2 ⁇ -alky-thio/alkyl-sulfinyl/ and alkyl-sulfonyl compounds of the invention starting from the 2 ⁇ -iodo-cyclopropylether or -cyclopropylamino compound [28].
  • the alkyl thioether [29] may be created by reaction with the corresponding alkali metal salt of the alkyl thiol in a suitable solvent, as is known.
  • the methyl thioether may be created by employing sodium thiomechoxide (sodium methyl sulfide; sodium methanethiolate) in ethanol.
  • the sulfoxide [30] and sulfone [31] can then be created as in Scheme E.
  • Scheme H 1 represents a synthesis for the creation of the 7 ⁇ -alkyl compounds of the invention starting from 17 ⁇ -hydroxy-androst-5-en-3-ol 3-acetate [32].
  • compound 32 is first protected by any suitable protecting agent.
  • any suitable protecting agent for example, t-butyldimethylsilyl chloride and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in methylene chloride.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • the protected acetate [33] is then C 7 -oxidized to create the 7-ketone [34] by any known means.
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • the 7-ketone is then reacted with the appropriate Grignard to give the corresponding 7-alkyl-7-alcohol [35].
  • the 7-ethyl-7-alcohol may be formed by reaction with ethylmagnesium chloride in THF.
  • the 7-aryl-7-alcohol can be formed by reaction with 4-bromotolylmagnesium chloride in THF.
  • the 7-substituted-7-alcohol [35] is dehydrated to the 7-alkyl diene [36] by reaction in a suitable matter, such as for example, by reaction with aluminum isopropoxide in the presence of toluene and cyclohexanone.
  • a suitable matter such as for example, by reaction with aluminum isopropoxide in the presence of toluene and cyclohexanone.
  • the diene [36] can then be hydrogenated and isomerized under known conditions to give the olefin [37]. For example, reaction with dry ammonia and lithium metal in t -butanol and toluene.
  • the olefin [37] can be isomerized and desilyated to the 4-en-17-alcohol [38] by any appropriate reagents. For example, reaction with 1,8-diazabicyclo[5.4.0]undec-7-ene at reflux followed by cooling to room temperature and reaction with tetrabutylammonium fluoride. Under Route A, compound [38] is then oxidized, lactamized and hydrolyzed as described in Scheme A to give the 4-aza-17-alcohol [39], which can then be etherified and cyclopropanated as in Scheme A to give the corresponding cyclopropyl ether [40].
  • the 17-alcohol [39] can be oxidized to the ketone [41] and then cycloaminated and reduced as in Scheme C, Route B.
  • the cyclopropylamine can be prepared from the 17-alcohol [38] with fewer synthetic steps by performing the oxidative ring cleavage, lactamization, cycloamination and reduction as described in Scheme C.
  • Route A (not shown in Scheme H 2 ).
  • Scheme I graphically describes a synthesis for the 7-hydroxy-, 7-oxo- and 7-alkanoyloxy- 17 ⁇ -cyclopropyl ether compounds of the invention from 3 ⁇ -acetoxy-17 ⁇ - t -butyldimethylsilyloxy-androst-5-en-7-one [34].
  • Compound [34] is ketalised under appropriate known reaction conditions, such as, for example reaction with 1,2-bis(trimethylsiloxy)ethane and trimethylsilyl trifluoromethanesulronate in methylene chloride at -78°C, to give the 7-ketal 3-acetate [43].
  • the cyclopropyl ether [46] can be reduced directly into the 7-alcohol [48], as is indicated in Option A, or it can first be hydrogenated to compound [47] and subsequently reduced, as indicated in Option B.
  • the reduction conditions may be similar to those used in previous Schemes, for example, sodium borohydride in ethanol and THF.
  • the hydrogenation may also be carried out in a manner similar to that described previously (Scheme B), for example, heating in the presence of hydrogen and palladium catalyst.
  • the cyclopropylether 7-alcohol [48] may be esterified into alkyl alcohol esters [49] by reaction with the appropriate alkyl anhydrides.
  • compound [48] is reacted with propionic anhydride in pyridine. Baer, H.H. et al., Can.J. Chem. 1991, 69, 1563-1574.
  • Suitable reaction conditions include, for example, treatment with lithium diisopropylamide in THF at -78°C followed by addition of t -butyldimethylsilyl chloride. Once this reaction product is worked-up, it can be acid hydrolyzed with acetic acid in THF to give the 17-alcohol-7-protected ether [51]. Compound [51] can then be oxidized, cycloaminated and reduced as in Scheme C, Route B to give the protected cyclopropylamine [52].
  • Scheme K graphically illustrates a potential preparation of the 7-alkoxycarbonylmethyl and 7-carboxymethyl compounds of the invention starting from compound [50], also an intermediate in Scheme J.
  • the protected 7-ketone [50] is carboxylated to form the alkylcarbonyloxymethyl diene [57] depicted.
  • the 7-ethyl methylcarboxylate may be created by reaction with triethyl phosphonoacetate in THF and sodium hydride.
  • the diene [57] can then be desilylated and hydrogenated to the 17-alcohol [58] in the typical manner, such as by treatment with tetrabutylammonium fluoride in THF.
  • the 17-alcohol [58] can be converted to the cyclopropylether [59], depicted under Option A, similarly as described in Scheme A.
  • the 17-alcohol [58] may be converted into the cyclopropylamine [59], depicted under Option B, similarly as described in Scheme C.
  • Compound [59] then may be base hydrolyzed in the conventional manner (Scheme A) to give the 7-ethanoic acid [60].
  • Scheme L graphically illustrates a synthesis of the 7-alkoxycarbonyl and 7-carboxylic acid compounds of the present invention starting from the 7-alkyl ethanoate [58], also an intermediate in Scheme K.
  • the carbonyl is phenylated in the conventional manner, for example, by reaction with phenylmagnesium chloride (4 molar eq.) in THF to give the 7-diphenyl-methyl alcohol [61].
  • This compound [61] can then be dealkylated to the 7-acid [62], as is known.
  • reaction with chromium trioxide (chromic acid) in water, methylene chloride and acetic acid Riegel, B. et al. Org. Synth. Coll. Vol.
  • the 7-acid [62] may then be converted into the alkyl ester [63], as is known.
  • the ester [63] can then be converted into either the cyclopropylether [64A] (Scheme A) or the cyclopropylamine [648] (Scheme C) as has been described previously.
  • Compound [64] may subsequently be base hydrolyzed in the conventional manner (e.g. NaOH in water, ethanol and/or THF) to the 7-acid [65].
  • Scheme M illustrates the preparation of the 7 ⁇ -ketone compounds of the invention starting from the 7-alkyl ester [63].
  • the ketone [63] is first reduced to the corresponding alcohol in the conventional manner (e.g., sodium hydride in ethanol), and silylated as in Scheme H 1 to give the protected ester [66].
  • the ester [66] is then reduced to the 7-methyl alcohol [67].
  • Suitable reduction conditions include, for example, lithium borohydride in THF. Jeanloz, R.W. & Walker, E. Carbohydrate Res. 1967, 4, 504 and Walker, E.R.H. Chem. Soc. Rev. 1976, 5 , 23-50.
  • the alcohol is then oxidized into the 7-aldehyde [68].
  • Suitable oxidation conditions include, for example, 4-hydroxy-TEMPO benzoate in methylene chloride and sodium bicarbonate followed by sodium bromite. Inokuchi, T. et al., J. Org. Chem. 1990, 55 , 462-466.
  • the 7-aldehyde [68] is then alkylated which is then oxidized and desilylated in the conventional manner (Schemes C and J, respectively) to give the 17-hydroxy-7-alkanone [69].
  • titanium tetrachloride and tetraethyl lead are sequentially added at -78°C in methylene chloride. Yamamoto, T. and Tamada, J.I. J. Am. Chem.
  • Compound [70] can then be prepared as the cyclopropyl ether (Option A, Scheme A) or as the cyclopropylamine [70].
  • the 7-alkanoyl group In the preparation of the cyclopropylamine, the 7-alkanoyl group must first be protected by suitable means, such as by formation of the ethylene or 2,2-dimethyl propane ketal, followed by the steps described in Option B, Scheme C, and subsequent deprotection.
  • the protection may be effected, for example by ethylene glycol or 2,2-dimethyl-propan-1,3-diol, respectively, with acid catalysis and deprotected under acid conditions taking care to minimize reaction with the acid-sensitive C 17 -cyclopropylamine, as is known.
  • Scheme N graphically illustrates a potential synthesis for the C 16 -alkenyl and C 16 -alkyl compounds of the invention, starting from androstenedione (androst-4-ene-3,17-dione) [72].
  • Compound [72] is treated in a manner similar to the procedure described in Scheme C to create the aza-androstenedione [11].
  • the dione can then be C 16 -alkylated by known techniques to give the 16-alkenyl dione [73].
  • diethyl oxalate and sodium methoxide are sequentially added in methylene chloride solvent at 0°C, followed by reaction with methyl iodide at 55°C, and finally treatment with sodium methoxide.
  • the alkenyl dione [73] can then be transformed into the cyclopropylether (Scheme A) or the cyclopropylamine (Scheme C) as previously described to give the 16-alkene [74].
  • the 16-alkene [74] may then be hydrogenated in the conventional manner, [Scheme B] to give the 16-alkane [75].
  • Scheme O 1 graphically represents the first part of a synthesis for the preparation of the 15-alkyl compounds of the invention starting from dehydroisoandrosterone 3-acetate (3 ⁇ -acetoxy-5-androsten-17-one).
  • the 3-acetoxy-17-one [76] can be ketalized at the C 17 position in the conventional manner (Scheme I) to give the 17-ketal [77].
  • the ketal [77] is ⁇ -brominated to give the 16-bromide [78].
  • Suitable bromination conditions include, for example, pyridinium bromide perbromide in dry THF, followed by treatment with sodium iodide, then reaction with sodium thiosulfate in water and pyridine.
  • the bromide [78] can then be dehydrogenated and 17-hydrolyzed into the 15-en-17-one.
  • Typical dehydrogenation conditions include, for example, potassium t -butoxide in dimethylsulfoxide.
  • Typical hydrolysis conditions include, for example, p -toluenesulfonic acid monohydrate.
  • the ketone, prepared by hydrolyzing the ketal can then be silylated in the conventional manner (Scheme H 1 ) to give the silylated diene [79].
  • the silylated diene [79] can then be selectively alkylated at C 15 to give the 15-alkyl silylated 17-ketone [80], as is known in the art.
  • compound [79] may be dropwise added to ethylmagnesium chloride in ether previously treated with cuprous chloride in THF.
  • the silyated ketone [80] may then be deprotected and oxidized in the conventional manner (Scheme I, Scheme H 1 [35] to [36], respectively) to give the alkylated dione [81].
  • the alkylated dione [81] is then converted into the seco acid (ring cleaving) and ring closure in the typical manner, as described in Scheme C to give the aza-dione [82].
  • Scheme O 2 represents the second part of the synthesis of the 15-alkyl compounds of the invention.
  • the aza-dione [82] can be directly converted (Route B) into the desired cyclopropyl ether [84A] (Option A) or cyclopropylamine (Option B) [84B] in the conventional manner (Scheme A. and Scheme C, respectively).
  • the aza-dione can be hydrogenated (Route A), under typical conditions (Scheme N) to give the 15-alkyl-aza-androstane [83], which can be converted into either the cyclopropylether [84A] or cyclopropylamine [84B] as described before.
  • the 7-alkyl compounds of the invention may be prepared in a manner analogous to that described in PCT applications PCT/US/04643 (WO 93/23420) and PCT/US/04734 (WO 93/23039) the disclosures of which are hereby incorporated by reference.
  • the compounds of the invention wherein there is a halogen substituent at the 2-position may be prepared by the method described in European Patent Application 0473225 A2 (91-202135), the disclosure of which is herein incorporated by reference.
  • Assays contained 0.05 M potassium phosphate buffer, pH 7.4, an NADPH regenerating system (1 mM NADPH, 5 mM glucose-6-phosphate, 1 IU/mL glucose-6-phosphate dehydrogenase), test compound, substrate and microsomal protein in a total volume of 0.2 mL.
  • Control assays contained all components, including dimethyl sulfoxide, but not test ccmpound. All assays were performed in duplicate. The test compound was incubated with 20 to 62 ⁇ g/mL microsomal protein, buffer, and the NADPH regenerating system described above at 34°C for 0 or 40 minutes.
  • Carrier steroids representing substrates and produces (17 ⁇ -hydroxypregnenolone, dehydroepiandrosterone, and androst-5-ene-3 ⁇ ,17 ⁇ -diol) and 0.8 mL of distilled, deionized water were also added at this time.
  • the steroids were extracted by the method of Moore and Wilson ( Methods in Enzymol ., eds. O. Malley, B.W. and Hardman, J.G. 36, 1975, pp. 466-474).
  • the organic phase containing the steroids was evaporated using nitrogen gas, the residues dissolved in 18% tetrahydrofuran (v/v) in hexane, and the steroids were separated by HPLC on a Si60 (5 ⁇ m) column (250 x 4 mm) using a gradient of 18-22% tetrahydrofuran (v/v) in hexane. Radioactivity in the steroid peaks was measured using a Radiomatic® Model ES or Model A515 Flo-One® detector.
  • the enzyme activity for each assay was calculated from the percent conversion of substrate to products, and the results were expressed as percent inhibition of control. The following results were obtained, wherein the values indicated are the mean of duplicate determinations: In Vitro C 17,20 Lyase Inhibition Compound Conc.
  • the steroids were then separated by normal phase HPLC on a LiCrosorb® DIOL derivatized silica gel column (10 ⁇ m; 4 x 250 mm) with a 3% to 7.5% isopropanol in hexane gradient, followed by isocratic conditions of 75% (v/v) isopropanol in hexane. Radioactivity in the steroid peaks was measured using a Packard Radiomatic model HS Flo-One detector. When the compound were tested using the above procedures with cynomolgus monkey 5 ⁇ -reductase, the following results were obtained: In Vitro 5 ⁇ -Reductase Inhibition Results Compound Conc.
  • mice Male Copenhagen rats and male athymic nude mice obtained from Harlan Laboratories, Indianapolis, IN, were divided into groups of 5 to 6 based on weight. Average weight was 100-140 g each for rats and 18-35 g each for the mice. Prior to oral dosing, animals were fasted overnight. Test compound was prepared by micronization in a lecithin vehicle using a glass Teflon® pestle-type homogenizer. The compound was brought to volume using lecithin so as to administer 0.5 mL per 100 g animal.
  • Rats and nude mice were given vehicle only (controls) or vehicle plus test compounds peros. Rats were also given the compound in lecithin or lecithin alone subcutaneously. Each group consisted of 5-6 animals. At a specified time after dosing, the animals were anesthetized with CO 2 gas, sacrificed by cervical dislocation, testes were excised, capsules were removed, and the tissue was weighed. Two volumes (w/v) of 0.05 M potassium phosphate buffer, pH 7.2, was added to the rat testes tissue on ice, and 11 volumes (w/v) of the same buffer were added to the mouse testes. Tissue was then homogenized using 20 strokes with a Dounce homogenizer equipped with a tight pestle.
  • Nude mouse testes lyase was assayed by the same procedure described for the rat enzyme above except that the 10,000 x g supernatant was diluted 12-fold in phosphate buffer, and 60 ⁇ L of this was used in the assay resulting in a 40-fold overall dilution of the supernatant.
  • Assays were terminated, extracted and analyzed as described above except that carrier steroids were 17 ⁇ -hydroxyprogesterone, androst-4-ene-dione, and testosterone.
  • the organic phase containing the steroids was evaporated using nitrogen gas, the residues dissolved in 18% tetrahydrofuran (v/v) in hexane, and the steroid substrate, 17 ⁇ -hydroxyprogesterone, and products (AED, TEST) were separated by HPLC on a Si60 (5 ⁇ m) column (250 x 4 mm) using 20% (v/v) tetrahydrofuran (THF) in hexane for 20 minutes then ramping to 60% THF (v/v) for 11 minutes.
  • Activity of test compound was expressed as percent inhibition relative to the control and was the mean of each group of treated animals.
  • MDL 103,432 inhibited nude mouse testicular C 17,20 lyase activity by 88% at 30 mg/kg and 96% at 100 mg/kg 4 hours after oral dosing.
  • Rat testicular C 17,20 lyase activity was inhibited by MDL 103,432 as shown below: Ex Vivo C 17,20 Lyase Inhibition Results Dose Time (hr) Route % Inhibition 50 mg/kg 4 p.o. 66.4 50 mg/kg 24 p.o. 52.7 50 mg/kg 4 s.c. 32.9 50 mg/kg 24 s.c. 40.7
  • the rats were anesthetized using sodium pentobarbital and the hair was clipped from the back dorsal area.
  • Tumors from donor Copenhagen rats were cut into fragments of 10 mm 3 and implanted subcutaneously (one site per rat) into the prepared dorsal area.
  • Animals were selected (105 days post implantation) for the treatment phase based on tumor size. Ten animals were anesthetized with sodium pentobarbital and bilaterally castrated. The remaining animals were assigned to treatment groups (ten per group) based on mean group tumor size. Animals were kept separate throughout the study. The tested compounds were prepared in solution or suspension in a lecithin vehicle (L- ⁇ -phosphatidylcholine type XV-E) containing methylparaben and propylparaben. All treatments were performed by oral gavage (per os) at 2 cc/kg each day of study. Tumor size and rat body weights were recorded every seven days over a period of 35 days.
  • lecithin vehicle L- ⁇ -phosphatidylcholine type XV-E
  • Table 4 indicates the average daily growth rate, measured from the corrected mean tumor size on day 35 and day 0, comparing MDL 105831 and flutamide (MDL 15910), a known androgen receptor antagonist. MDL 105831 is shown to have similar tumor suppression properties as flutamide which is additive when combination therapy is employed.
  • Tumor-donating mice were first anesthetized using sodium pentobarbital and then sacrificed by cervical dislocation. The tumor was subsequently excised and placed in a petri dish containing ice-cold Hanks balanced salt solution. Tumors were cut into 2-3 mm cubes for implantation. Recipient animals were first anesthetized with 50 mg/kg pentobarbital, then implanted, by use of a trocar, with tumor fragments (one per mouse) in the dorsal area. Animals were separated into two control groups, one with vehicle alone and the other castrated, and the treatment groups, where n is the number of animals in each group.
  • mice were selected for treatment groups based on tumor size. Each test compound was prepared as a solution or suspension in a lecithin vehicle (L- ⁇ -phosphatidylcholine type XV-E) containing methylparaben and propylparaben at a dose volume of 10 cc/kg. Animals were treated for 42 days by oral gavage (per os) seven days per week. Twenty-four hours after the last treatment the animals were euthenized by CO 2 and tumors were removed and weighed. During the study period, mice were weighed and palpated weekly for tumors. In Table 5, average tumor growth is determined from the corrected group means over a 28 day period after treatment was started.
  • a lecithin vehicle L- ⁇ -phosphatidylcholine type XV-E
  • the correction was determined by first eliminating those animals from each data set which exhibited grossly disproportionate growth relative to the other animals in the treatment group. Such tumor growth is believed to result from conversion of the tumor into a non-androgen dependent sarcoma and most often resulted in euthanasia of the subject before the end of the treatment period.
  • the following animal data was deleted before computation of the corrected mean data in Table 5, Fig. 1: animals 4 and 44; Fig. 2: animals 10, 38 and 42; Fig. 3: Animal 39; Fig. 4: Animals 8, 9 and 49; Fig. 5: Animals 37 and 40 and 41.
  • Table 5 illustrates the average tumor growth in animals treated with 4-aza-17 ⁇ -(cyclopropyloxy)-5 ⁇ -androstan-3-one (MDL 103432; 50 mg/kg B.I.D.) 4-aza-17 ⁇ -(cyclopropylamino)-androst-5(6)-en-3-one (MDL 105831; 50 mg/kg B.I.D.) and flutamide (MDL 15,910; 15 mg/kg B.I.D.), a known androgen receptor antagonist.
  • MDL 103432 4-aza-17 ⁇ -(cyclopropyloxy)-5 ⁇ -androstan-3-one
  • MDL 105831 4-aza-17 ⁇ -(cyclopropylamino)-androst-5(6)-en-3-one
  • flutamide MDL 15,910; 15 mg/kg B.I.D.
  • room temperature means 18°C-23°C
  • any reference to “overnight” means 14-18 hours and soluted reagents are in aqueous solutions.
  • testosterone (UPJOHN, 9.16297 g, 31.772 mmol) is dissolved into tert -butyl-alcohol (300 mL) in a 1000 mL 3-necked, round bottomed flask. Potassium carbonate (K 2 CO 3 ) in water (75 mL) is added and stirred until completely dissolved.
  • K 2 CO 3 Potassium carbonate
  • the reaction flask is fitted with a 500 mL dropping funnel charged with sodium metaperiodate (NaIO 4 , ALDRICH, 40.9249 g, 191.34 mmol) in water (350 mL).
  • the reaction flask is also fitted with a separate 125 mL dropping funnel charged with a solution of potassium permanganate (FLUKA, KMnO 4 , 0.80424 g, 5.089 mmol) in water (50 mL).
  • reaction mixture is then filtered through Celite® filter aid and stored overnight at room temperature.
  • the filtrate is concentrated to about 250 mL under reduced pressure (45 mm Hg, 70°C) and transferred to a 500 mL seperatory funnel.
  • the concentrate is acidifed with 10% sulfuric acid (H 2 SO 4 , 26 mL) and extracted(3 x 200 mL) ether
  • the combined ethereal extracts are washed with 100 mL diethyl ether, then poured into 10% sulfuric acid (300 mL) in order to precipitate the product.
  • the precipitate is extracted (4 x 200 mL) with methylene chloride (CH 2 Cl 2 ), the organic phases combined and washed with brine (100 mL), dried over MaSO 4 , filtered and evaporated to dryness to give a white solid.
  • the material was recrystallized overnight from acetone (about 50 mL), collected by filtration, washed in hexane (30 mL) and dried under reduced pressure (0.3 mmHg, room temperature) for 4.5 hours to give 17 ⁇ -hydtoxy-5-oxo-4-nor-3,5- seco -androstane-3-carboxylic acid (6,1247 g).
  • the compound has the following structure:
  • the 4-nor-3,5- seco -acid can be prepared in the following manner.
  • Testosterone (9.1863 g) is dissolved in CH 2 Cl 2 (70 mL) and diluted with methanol (100 mL). The solution is chilled to -78°C under nitrogen. Ozone is then bubbled through the chilled solution for 25 minutes, after which the solution turns green. The atmosphere of the reaction vessel is purged with nitrogen, the reaction mixture is warmed to room temperature and the solvent evaporated.
  • the precipitate is recrystallized from ethanol by adding it to boiling ethanol (350 mL), concentrating ( ⁇ 180 mL) and drying (reduced pressure, room temperature) to give 17 ⁇ -acetoxy-4-aza-androst-5(6)-en-3-one and corresponds to the chemical formula:
  • the crude product is recrystallized from ethanol to give colorless crystals (0.3132 g, 1.0822 mmol) of 17 ⁇ -hydroxy-4-aza-androst-5(6)-en-3-one.
  • the mother liquor is concentrated and the recrystallization procedure above repeated in order to give a second crop of crystals. (0.3945 g, 1.363 mmole).
  • the 17(3-alcohol prepared in Example 1C (2.20 g, 7.77 mmol) is prepared into a slurry with chloroform (CHCl 3 , 30 mL) and ethyl vinyl ether (CH 2 CHOC 2 H 5 , 40 mL).
  • Mercuric acetate (ALDRICH, Hg(OCCCH 3 ) 2 , 2.4869 g, 7.804 mmol) is added to the reaction vessel which is then purged with nitrogen and heating to reflux under a nitrogen atmosphere.
  • the slurry is stirred at 0°C for 10 minutes and methylene iodide (CH 2 I 2 , ALRICH, 2.20 mL, 7.32 g, 27.3 mmol) is added in small portions over 15 minutes and the slurry is stirred continuously at 0°C under nitrogen. Another portion of chloroform (CHCl 3 , 40 mL) is added, and stirring is continued at 0° for a total reaction time of 6 hours.
  • the reaction mix is poured into 120 mL of a saturated solution of NH 4 Cl and extracted with EtOAc (200 mL).
  • 17 ⁇ -Acetoxy-4-aza-5 ⁇ -androst-5(6)-en-3-one (10.0404 g, 30.2914 mmol) and palladium/carbon catalyst (ENGELHARD, 1.2642 g, 5% Pd on carbon) are placed into a 500 mL Parr bottle.
  • the reaction container is purged with nitrogen and ethanol (250 mL) is added.
  • the reaction container is then charged with hydrogen to 60 p.s.i. and heated to 60°C with mechanical agitation. At the increased temperature, the pressure or the reaction vessel increases, but then upon reaction with the steroid it decreases.
  • the hydrogen pressure is maintained at around 60 p.s.i. by periodic additions of gas through a ballast tank until the hydrogen pressure becomes constant (about 90-100 hours).
  • the reaction mixture Upon completion or the reaction, the reaction mixture is cooled to room temperature, washed through Celite® with acetic acid (70 mL), filtered and concentrated to dryness to give the crude product.
  • the crude product is recrystallized from ethanol (150 mL) by dissolving in boiling solvent (400 mL) and concentrating. The colorless crystals are collected and dried overnight under reduced pressure (0.4 mm Hg) at room temperature and analyzed for purity to give 17 ⁇ -acetoxy-4-aza-5 ⁇ -androstan-3-one. Yield 25.08 mmol, 83%.
  • the compound has the following structure:
  • 4-aza-17 ⁇ -vinyloxy-androstan-3-one (0.5297 g, 1.817 mmol) is made into a slurry with CH 2 Cl 2 (15 mL) and ethyl vinyl ether (CH 3 CH 2 OCHCH 2 , ALDRICH, 11.31 g, 156.8 mmol).
  • Mercuric acetate Hg(OOCCH 3 ) 2 , ALDRICH, 0.6030 g, 1.8922 mmol
  • Glacial acetic acid (HOOCCH 3 , EM, 0.050 mL, 0.053 g, 0.873 mmol) is added and the reaction mixture is cooled to room temperature while stirring overnight.
  • the reaction is worked-up by pouring it into 5% aqueous sodium hydroxide (15 mL) and hexane (40 mL). The layers are separated and the organic phases washed with brine (2 x 24 mL). The combined organic phases are washed, filtered and evaporated to give 17 ⁇ -vinyloxy-4-aza-5 ⁇ -androstan-3-one (1.0581 g) which was immediately used in the following step without further characterization.
  • Example 2C 4-Aza-17 ⁇ -vinyloxy-5 ⁇ -androstan-3-one (1.817 mmol) prepared in Example 2C is dissolved into a cosolvent system of CH 2 Cl 2 (12 mL) and methyl tert-butyl ether (12 mL) and chilled to 0°C under nitrogen. Diethyl zinc ((CH 3 CH 2 ) 2 Zn) is added, followed by methylene iodide (CH 2 I 2 , ALDRICH, 1.80 mL, 5.96 g, 22.3 mmol) which is added in small portions over 2 minutes. The mixture is stirred at 0°C under nitrogen for 6 1/4 hours.
  • the product has the following formula:
  • 17 ⁇ -hydroxy-5-oxo-4-nor-3,5- seco -androstane-3-carboxylic acid (3.1856 g, 10.329) prepared in Example 1A or otherwise obtained is made into a slurry with methylamine hydrochloride (CH 3 NH 2 ⁇ HCl, ALDRICH, 7.4847 g, 110.9 mmol) and HOAc (80 mL) and heated to reflux under nitrogen. After six days, the reaction is cooled to room temperature and the reaction is concentrated (30 mm Hg, 55°C) to give a thick slurry.
  • methylamine hydrochloride CH 3 NH 2 ⁇ HCl, ALDRICH, 7.4847 g, 110.9 mmol
  • HOAc 80 mL
  • Example 3C The vinyl ether prepared in Example 3C (4-methyl-17 ⁇ -vinyloxy-4-aza-androst-5(6)-en-3-one, 3.05 mmol) is dissolved into a mixture of CH 2 Cl 2 (20 mL) and t -butyl methyl ether (20 mL) and chilled to 0°C under nitrogen. Diethyl zinc ((CH 3 CH 2 ) 2 Zn, ALDRICH, 20.0 mL, 1.1 M in toluene, 22.0 mmol) is added followed by charging with, in small portions, methylene iodide (CH 2 I 2 , ALDRICH, 1.80 mL, 5.96 g, 22.3 mmol).
  • Diethyl zinc ((CH 3 CH 2 ) 2 Zn, ALDRICH, 20.0 mL, 1.1 M in toluene, 22.0 mmol) is added followed by charging with, in small portions, methylene iodide (CH 2 I 2 , ALDRICH, 1.80
  • 17 ⁇ -Acetoxy-4-aza-5 ⁇ -androst-1-en-3-one (0.500 g, 1.508 mmol) is dissolved in warm ethanol (20 mL). 6M sodium hydroxide (10 mL) is added and the reaction is stirred for 16 hours at room temperature. The reaction is diluted with EtOAc (50 mL) extracted with brine (3 x 100 mL), and dried over MgSO 4 to give 17 ⁇ -hydroxy-4-aza-5 ⁇ -androst-1-en-3-one (0.4570 g) and a minor impurity. The reaction product is carried onto the next synthesis without further purification.
  • reaction is quenched with acetic acid (EM, 0.346 g, 5.76 mmol) and stirred for 1 hour.
  • EM acetic acid
  • the reaction is diluted with 10% sodium hydroxide (25 mL), extracted with brine (2 x 25 mL) filtered and dried to give 17 ⁇ -vinyloxy-4-aza-5 ⁇ -androst-1-en-3-one (0.6906) in quantitative yield which is carried onto the next step without further purification.
  • the compound has the following structure:
  • Testosterone (8.7813 g, 30.45 mmol) is dissolved into a mixture of CH 2 Cl 2 (50 mL) and methanol (10 mL) and the solution is chilled to -78°C under nitrogen while stirring. Ozone is bubbled through the reaction while maintaining temperature and stirring for 3 hours. Note tnat after 30 minutes the reaction color turns blue. The reaction is slowly brought to room temperature, while replacing the ozone with nitrogen. The solvent is evaporated and the residue is taken-up in ether (200 mL) and extracted with 10% sodium hydroxide (3 x 50 mL), noting gas evolution. The alkaline phases are combined and washed again with ether (50 mL).
  • the seco acid prepared in Example 5A (8.14 g, 26.56 mmol) is dissolved into HOAc (100 mL).
  • Ammonium acetate (NH 4 OOCCH 3 , 15.6931 g, 203.6 mmol) is added and the reaction mix is heated to reflux under nitrogen. After 69 hours, the reaction is cooled to room temperature and is poured into ice water (700 mL), whereupon the product separates as a tarry mass.
  • the solution is diluted with brine (200 mL) and extracted with EtOAc (3 x 200 mL).
  • the organic phases are combined and washed with brine (2 x 200 mL), with water (3 x 200 mL) and with saturated NaHCO 3 (2 x 100 mL).
  • the extract is dried over MgSO 4 , filtered and the solvent evaporated to give the crude product of the title compound.
  • the product is recrystallized from ethanol to give 4-aza-androst-5(6)-ene-3,17-dione with traces of the C 17 -acetate (1.0859 g, 3.778 mmol). A second recrystallization of the mother liquor gives additional compound (0.5431 g). Total Yield: 21%.
  • the desired product has the following structure:
  • the compound has the following structure:
  • Androst-4-ene-3,17-dione (10.000 g, 34.914 mmol) is dissolved in a mixture of CH 2 Cl 2 (100 mL) and EtOAc (100 mL), and the solution is chilled to -78°C under nitrogen. Ozone is bubbled below the surface of the solution through a coarse glass frit until the reaction mixture turns deep blue. The -78°C reaction mixture is then sparged with dry nitrogen until the blue color dissipates. The solution is allowed to warm to ambient temperature and the solvent removed under reduced pressure. The residue is taken up in ether (250 mL) and the product extracted with 10% sodium hydroxide (3 x 25 mL).
  • the combined basic extracts are washed with fresh ether (100 mL), then acidified with 10% sulfuric acid (H 2 SO 4 ; 100 mL).
  • the acidic aqueous solution is then extracted with CH 2 Cl 2 (4 x 50 mL).
  • the combined CH 2 Cl 2 extracts are washed once with brine (50 mL), dried over MgSO 4 , filtered and the solvent is evaporated under reduced pressure to give the title compound.
  • reaction solution is filtered through silica gel (1:1 EtOAc/CH 2 Cl 2 ), and carefully purified by flash chromatography (1:1 EtOAc/CH 2 Cl 2 ) to give 4-aza-5 ⁇ -androstan-3,17-dione.
  • reaction solvent is removed under reduced pressure and the residue is redissolved in EtOAc (500 mL).
  • organic solution is washed with 5% sodium hydroxide (400 mL) and brine (400 mL), then dried over MgSO 4 , filtered and concentrated under reduced pressure.
  • the reaction product is further purified by flash chromatography (1:1 EtOAc/CH 2 Cl 2 ) to give the title compound.
  • the acidified reaction mixture is stirred at room temperature for 2 hours, then diluted with hexane (500 mL).
  • the organic solution is extracted with 10% sodium hydroxide (300 mL) and brine (2 x 200 mL), dried over MgSO 4 , filtered, and evaporated to dryness to obtain 17 ⁇ -vinyloxy-4-methyl-4-aza-androst-1-en-3-one which is used without further purification in the following synthesis.
  • 17 ⁇ -vinyloxy-4-methyl-4-aza-androst-1-en-3-one (8.000 g, 24.279 mmol) prepared in the previous paragraph is dissolved into a mixture of CH 2 Cl 2 (100 mL) and methyl t-butyl ether (100 mL), and then chilled to O°C under a nitrogen atmosphere. Diethylzinc solution (1.1 M in toluene; 145 mL, 159.5 mmol) is added to the steroid solution with stirring, followed by cautious, dropwise addition of CH 2 I 2 (13.00 mL, 161.4 mmol). The O°C reaction mixture was stirred for 2.5 hours, then allowed to warm to room temperature over 14 hours.
  • Sodium hydride 50% dispersion in mineral oil, 0.580 g, 12.08 mmol is washed with hexane (3 x 25 mL) under an inert atmosphere to remove the mineral oil.
  • Anhydrous tetahydrofuran (THF, 50 mL) is cautiously added while maintaining the inert atmosphere.
  • a solution of thiophenol (1.230 mL, 11.98 mmol) in THF (50 mL) is slowly added dropwise over 30 minutes, while stirring, as gas is given off. At the end of the addition, the THF solution is heated to reflux for 30 minutes and then allowed to cool to room temperature.
  • N-bromosuccinimide (2.360 g, 13.259 mmol) and diethylaminosulfur trifluoride (0.880 mL, 6.661, mmol) under an inert atmosphere are sequentially added and the reaction mixture is stirred at 0°C for 4.5 hours, then poured into saturated aqueous NaHCO 3 (50 mL) and extracted with CH 2 Cl 2 (3 x 50 mL). The combined organic extracts are washed with brine (100 mL), dried over MgSO 4 , filtered and evaporated to dryness. The product is purified by flash chromatography (1:1 EtOAc/CH 2 Cl 2 ) to give 2-bromo-17 ⁇ -cyclopropyloxy-1-fluoro-4-methyl-4-aza-5 ⁇ -androst-1-en-3-one.
  • 17 ⁇ -Trimethylsilyloxy-4-aza-5 ⁇ -androstan-3-one from Example 11A (10.000 g, 27.517 mmol) is prepared in solution with toluene (100 mL). N,N,N',N'-tetramethylethylenediamine ((CH 3 ) 2 NCH 2 CH 2 N(CH 3 ) 2 , TMEDA, 12.50 mL, 82.824 mmol) is added under nitrogen. The solution is chilled to -37°C and tetramethylsilyl iodide (TMSI, 3.95 mL, 27.76 mmol) is added dropwise.
  • TMSI tetramethylsilyl iodide
  • the resulting slurry is stirred for 5 minutes and then bromine (7.00 mL, 135.87 mmol) is added dropwise.
  • the stirring reaction mixture is allowed to warm to 20°C, after which it is poured into saturated aqueous sodium sulfite (Na 2 SO 3 , 100 mL).
  • the biphasic mixture is extracted with EtOAc (100 mL), and the organic phases are combined and washed twice with Na 2 SO 3 (100 mL) and then with brine (2 x 100 mL).
  • the material is then dried over MgSO 4 , filtered and evaporated to dryness.
  • the mixture is allowed to warm to 20°C at which time it is poured into saturated aqueous sodium sulfite (Na 2 SO 3 , 100 mL).
  • the resulting biphasic mixture is extracted with EtOAc (100 mL), the organic phases are combined and washed with saturated aqueous sodium sulfite (Na 2 SO 3 , 100 mL) and brine (100 mL), dried over MgSO 4 , filtered, and evaporated to dryness.
  • the residue is redissolved in THF (100 ML), tetrabutylammonium fluoride (1M in THF; 28.00 mL, 28.00 mmol) is added, and the mixture is stirred at room temperature for 15 minutes.
  • the reaction is poured into saturated aqueous NH 4 Cl (100 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts are washed with brine (2 x 150 mL), dried over MgSO 4 , filtered and concentrated under reduced pressure. The crude product is purified by flash chromatography to give the title compound of purity sufficient for subsequent syntheses (1:1 EtOAc/CH 2 Cl 2 ).
  • Example 11D 17 ⁇ -Hydroxy-2 ⁇ -iodo-4-aza-5 ⁇ -androstan-3-one prepared in Example 11D or otherwise obtained is oxidized in a manner similar to the procedure described in Example 6D to give 2 ⁇ -iodo-4-aza-5 ⁇ -androstan-3,17-dione (the dione). The dione is then converted to the 17-cyclopropylimine and subsequently to the title compound in a similar manner as described in Example 6E.
  • Example 12A 17 ⁇ -cyclopropylamino-2 ⁇ -iodo-4-aza-5 ⁇ -androstan-3-one prepared in Example 12A or otherwise obtained which is converted into the corresponding title compounds in a manner similar to that described in Example 11F, 11G and 11H, respectively, to obtain the corresponding title compound.
  • Example 11B 17 ⁇ -Hydroxy-2 ⁇ -bromo-4-aza-5 ⁇ -androstan-3-one prepared in Example 11B or otherwise obtained is oxidized in a manner similar to that described in Example 6D to give 2 ⁇ -bromo-4-aza-5 ⁇ -androstan-3,17-dione (the dione). The dione is then converted to the 17-cyclopropylimine and subsequently to the title compound in a similar manner as described in Example 6E.
  • Example 13A 17 ⁇ -Hydroxy-4-methyl-4-aza-5 ⁇ -androstan-3-one prepared in Example 13A or otherwise obtained is oxidized into 4-methyl-4-aza-5 ⁇ -androst-3,17-dione (the dione) as described in Example 6D. The dione is then cycloaminated as described in Example 6E to give the title compound.
  • Example 14B 2 ⁇ -Bromo-17 ⁇ -trimethylsilyloxy-4-methyl-4-aza-5 ⁇ -androstant-3-one prepared as in Example 14B is hydrolyzed as in Example 11B to give 2 ⁇ -bromo-17 ⁇ -hydroxy-4-methyl-4-aza-5 ⁇ -androstan-3-one (17-alcohol).
  • the 17-alcohol is then oxidized and cycloaminated as in Examples 6D-6E, respectively, to give the title compound.
  • 3 ⁇ ,17 ⁇ -Dihydroxy-androst-5(6)-en-3-acetate (50.000 g, 150.38 mmol) obtained by treating 3 ⁇ -acetoxy-androst-5(6)-ene-17-one (available from ALDRICH, 39,008-9) with sodium borohydride, is dissolved in CH 2 Cl 2 (225 mL) with t -butyldimethylsilyl chloride (30.000 g, 199.0 mmol) under nitrogen. 1,8-Drazabicyclo[5.4.0]undec-7-ene (DBU, 33.00 mL, 220.7 mmol) is added dropwise to the CH 2 CH 2 solution, while keeping the temperature below reflux with an ice bath.
  • DBU 1,8-Drazabicyclo[5.4.0]undec-7-ene
  • reaction solution is diluted with EtOAc, (800 mL) and extracted with saturated aqueous NH 4 Cl (3 x 200 mL), brine (200 mL), saturated aqueous NaHCO 3 (200 mL) and once again with brine (200 mL).
  • the combined organic phases are dried over MgSO 4 , filtered and concentrated under reduced pressure to give the title compound of purity sufficient for subsequent synthesis.
  • Acetic anhydride 38.00 mL, 402.7 mmol
  • acetic acid 100.0 mL, 1746.8 mmol
  • t -butylchromate t -butylchromate
  • reaction product is extracted into EtOAc (3 x 500 mL) and the combined extracts are washed with saturated aqueous NaHCO 3 (3 x 500 mL) brine (500 mL), dried over MgSO 4 , filtered and concentrated to afford the crude product as a mixture of diastereomers which is carried onto the next step without further purification.
  • Example 16C In a manner similar to the procedure described in Eastham, J. & Teranishi, R., Org. Synth. Coll. Vol. IV, 1963, 192-195 and Dierassi C., Org. React., 1951, 6, 207-272 17 ⁇ -t-butyldimethylsilyloxy-7-ethyl-androst-5-en-3 ⁇ ,7-diol (35.000 g, 71.324 mmol) prepared in Example 16C, is dissolved in a mixture of toluene (700 mL) and cyclohexanone (200 mL).
  • the aqueous phase is extracted three times with CH 2 Cl 2 and the combined organic phases are washed with brine (2 x 100 mL), dried with MgSO 4 , filtered and concentrated under reduced pressure. The residue is recrystallized from ethanol to give the title compound.
  • the ammonia is allowed to evaporate from the reaction mixture under a stream of dry nitrogen while the reaction vessel is allowed to warm to room temperature.
  • the remaining toluene slurry is diluted with EtOAc (300 mL), washed with water (200 mL), washed again with brine (2 x 200 mL), dried over MgSO 4 , filtered and evaporated to dryness.
  • the residue is recrystalized from ethanol to give the title compound.
  • reaction mixture is diluted with EtOAc (500 mL) and washed with saturated aqueous NH 4 Cl (3 x 200 mL) and brine (200 mL), then dried over MgSO 4 , filtered, and evaporated to dryness. The residue is recrystalized from ethanol to give the title compound.
  • 7 ⁇ -Ethyl-17 ⁇ -hydroxy-androst-4-en-3-one (10.000 g, 34.914 mmol) is converted into 17 ⁇ -hydroxy-7 ⁇ -ethyl-5-oxo-4-nor-3,5-seco-androstane-3-carboxylic acid ( seco acid) as in Example 6A.
  • the seco acid is then converted into the ⁇ -lactam similarly to the procedure reported in Example 6B.
  • the ⁇ -lactam is then hydrolyzed to 7 ⁇ -ethyl-17 ⁇ -hydroxy-4-aza-androst-5-en-3-one in a manner similar as reported in Preparation 7C.
  • Example 16G 17 ⁇ -acetoxy-7 ⁇ -ethyl-4-aza-androst-5-en-3-one prepared in Example 16G, second paragraph is hydrogenated in a manner similar as in Example 6C to give the title compound.
  • Example 17 ⁇ -Hydroxy-7 ⁇ -ethyl-4-aza-5 ⁇ -androst-1(2)-en-3-one from Example 17C is C 17 -oxidized as described in Example 6D, then cycloaminated as described in Example 6E to give the title compound.
  • Example 17 ⁇ -Acetoxy-7 ⁇ -ethyl-5 ⁇ -androstan-3-one from Example 17A is hydrolyzed as in Preparation 7C, then C 17 -oxidized as in Example 6D, then cycloaminated as in Example 6E to give the title compound.
  • Trimethylsilyl trifluoromethanesulfonate (0.20 mL, 1.035 mmol) is added under an inert atmosphere, the reaction is stirred for three hours, pyridine (2.00 mL, 24.73 mmol) is added and the stirred mixture is allowed to warm to room temperature.
  • the organic solution is poured into saturated aqueous NaHCO 3 (300 mL) and the resultant biphasic solution is extracted with EtOAc (3 x 300 mL). The combined organic extracts are washed with brine (200 mL), dried over MgSO 4 , filtered and evaporated to dryness.
  • 7,7-Ethylenedioxy-17 ⁇ -hydroxy-androst-4-en-3-one is oxidized into 7,7-ethylenedioxy-17 ⁇ -hydroxy-5-oxo-4-nor-3,5- seco -androstane 3-carboxylic acid ( seco -acid) as described in Example 6A.
  • the seco -acid is converted into 7,7-ethylenedioxy-17 ⁇ -hydroxy-4-aza-androst-5-ene-3,7-dione ( ⁇ -lactam) in a manner similar to that described in Example 6B.
  • the ⁇ -lactam is hydrolyzed under conditions similar to those described under Preparation 7C to give 17 ⁇ -ydroxy-4-aza-androst-5-ene-3,7-dione.
  • 17 ⁇ -Hydroxy-4-aza-androst-5-ene-3,7-dione (40.000 g, 131.84 mmol) prepared in Example 18B or otherwise obtained is prepared in solution at -78°C in dry THF (300 mL).
  • Lithium diisopropylamide solution (2.0 M in heptane/THF/ethylbenzene; 135.0 mL, 270.0 mmol) is added under an inert atmosphere and the deprotonation reaction occurs while stirring at -78°C over 60 minutes.
  • Trimethylsilyl chloride (35.00 mL, 275.8 mmol) is added, and stirring is continued for an additional 15 minutes and then the solution is allowed to warm to room temperature.
  • Example 19A By the procedure described in Hart, J.W. et al., J. Chem. Soc. Chem. Commun ._1979, 156-157 17 ⁇ -trimethylsilyloxy-4-trimethylsilyl-4-aza-androst-5-ene-3,7-dione prepared in Example 19A (40.000 g, 92.644 mmol) is prepared in a -78°C solution in a mixture of THF, (300 mL) and hexamethylphosphoramide (30.0 mL, 172.4 mmol) and is reacted with lithium diisopropylamide (2.0 M in heptane/THF/ethylbenzene; 50.0 mL, 100.0 mmol) under an inert atmosphere.
  • the 17-alcohol is oxidized by application of the conditions described under Example 6D into 7-( t -butyldimethylsilyloxy)-4-aza-androst-5,7-diene-3,17-dione, which is then converted into 17 ⁇ -cyclopropylamino-7-( t -butyldimethylsilyloxy)-4-aza-androst-5,7-diene-3-one under conditions similar to those described under Example 6E.
  • the above 7-hydroxy steroids are obtained from selectively reducing the C 7 -carbon of the corresponding 7-oxo compounds, 17 ⁇ -cyclopropyloxy-4-aza-5a-androstan-3,7-dione, 17 ⁇ -cyclopropylamino-4-aza-androst-5-ene-3,7-dione and 17 ⁇ -cyclopropylamino-4-aza-5 ⁇ -androstan-3,7-dione, obtained in Examples 18D, 19C and 19D, respectively, by the procedure described in Example 20A.
  • a solution of sodium hydride (50% in mineral oil; 7.000 g, 145.8 mmol) is prepared in THF, (200 mL), and the solution is washed with hexane (3 x 30 mL).
  • Triethyl phosphonoacetate 28.7 mL, 144.7 mmol
  • a solution of 17 ⁇ -trimethylsilyloxy-4-trimethylsilyl-androst-5-ene-3,7-dione (32.406 g, 72.374 mmol) in THF is added, followed by stirring at room temperature for 6 hours under nitrogen.
  • the diene disilane prepared above is redissolved in THF (300 mL) and treated with tetrabutylammonium fluoride (1.0 M in THF; 35.0 mL, 35.0 mmol).
  • the desilylation reaction occurs over 20 minutes with stirring at ambient temperature.
  • the reaction mixture is then diluted with EtOAc (500 mL) and washed with brine (3 x 400 mL).
  • the crude product solution is dried over MgSO 4 , filtered and evaporated to dryness.
  • the crude product is purified by flash chromatography (1:1 EtOAc/CH 2 Cl 2 ) to afford 17 ⁇ -hydroxy-4-trimethylsilyl-7-ethyloxycarbonylmethylene-4-aza-androst-5-en-3-one as a mixture of the E and Z isomers (diolefin).
  • the diolefin is then hydrogenated in a manner similar to that described in Preparation 7H to give 7 ⁇ -ethoxycarbonylmethyl-17 ⁇ -hydroxy-4-aza-5 ⁇ -androstan-3-one.
  • the compound has the following structure:
  • Example 22A In a manner analogous to that reported in Riegel, B. et al, Org.Synth., Coll. Vol.3 , 1955, 234-236 and Subramaniam, C.S., et al., Synthesis , 1978, 468-469, 17 ⁇ -hydroxy-7 ⁇ -(diphenylhydroxymethyl)-4-aza-5a-androstan-3-one (8.000 g, 16.890 mmol) prepared in Example 22A is dissolved in a mixture Of CH 2 Cl 2 (60 mL) and acetic acid (60 mL), then is treated with a solution of chromium trioxide (chromic acid, CrO 3 ; 8.500 g, 85.01 mmol) in a mixture of water (6.0 mL) and acetic acid (40 mL) at room temperature.
  • chromium trioxide chromic acid, CrO 3 ; 8.500 g, 85.01 mmol
  • the reaction mixture is stirred 20 minutes and then acetic anhydride (34.0 mL, 360.3 mmol) is added.
  • the reaction solution is heated to a gentle reflux with stirring. After 20 minutes at reflux, the reaction is quenched by the cauticus addition of methanol (50 mL) then cooled to room temperature and concentrated to approximately 75 mL.
  • the concentrated solution is poured into ice water (500 mL), and the resultant precipitate is collected by filtration. The solid is recrystallized from ethanol to afford the title compound.
  • the reaction solution is then filtered through Celite® to remove any dicyclohexylurea which might precipitate.
  • the filtrate is evaporated to dryness and purified by flash chromatography (1:1 EtOAc/CH 2 Cl 2 ) to give the title compound.
  • the compound has the following formula:
  • the solution is diluted with CH 2 Cl 2 (150 mL) and washed with water (2 x 100 mL), saturated aqueous NaHCO 3 (2 x 100 mL), water (100 mL) and brine (100 mL).
  • the organic phase is then dried over MgSO 4 , filtered and evaporated to dryness.
  • the residue is purified by flash chromatography (1:1 EtOAc/CH 2 Cl 2 ) to give the title compound.
  • Example 22C 7 ⁇ -Ethoxycarbonyl-4-aza-5 ⁇ -androstane-3,17-dione prepared in Example 22C or otherwise obtained is reduced similarly as in Example 20A to obtain 7 ⁇ -ethoxycarbonyl-17 ⁇ -hydroxy-4-aza-5 ⁇ -androstan-3-one (17-alcohol).
  • the 17-alcohol is then silylated as in Example 16A to give 17 ⁇ - tert -butyldimethylsilyloxy-7 ⁇ -ethoxycarbonyl-4- tert -butyldimethylsilyl-4-aza-5a-androstan-3-one (protected alcohol).
  • the biphasic solution is chilled to 0°C and sodium bromite (NaBrO 2 , 1.700 g, 12.602 mmol) is added with vigorous stirring. After the bromite addition, the reaction mixture is allowed to warm to room temperature, and is stirred an additional 3 hours. The reaction is quenched with the dropwise addition of ethanol (1.00 mL, 17.04 mmol) and then the phases are separated. The aqueous phase is extracted with CH 2 Cl 2 (2 x 50 mL) and the combined organic layers are washed with brine (2 x 75 mL). The organic solution is dried over MgSO 4 , filtered, and evaporated to dryness. The reissue is purified by flash chromatography (1:1:2 EtOAC/CH 2 Cl 2 /hexane) to afford the title compound.
  • sodium bromite NaBrO 2 , 1.700 g, 12.602 mmol
  • TiCl 4 titanium tetrachloride
  • Et 4 Pb tetraethyl lead
  • the reaction mixture is then allowed to gradually warm to -30°C over 30 minutes.
  • the reaction is quenched, when the temperature reaches -30°, with methanol (10 mL) and saturated aqueous NaHCO 3 (10 mL).
  • the crude product solution is diluted with ethyl acetate (100 mL) and washed with saturated aqueous NaHCO 3 (2 x 50 mL) and brine (2 x 50 mL).
  • Example 24C 7 ⁇ -(1-Hydroxypropyl)-17 ⁇ - t -butyldimethylsilyloxy-4- t -butyldimethylsilyl-4-aza-5 ⁇ -androstan-3-one from Example 24C is oxidized in a manner as in Example 6D to obtain the title compound.
  • Example 24D 7 ⁇ -(1-Oxopropyl)-17 ⁇ - t -butyldimethylsilyloxy-4- t -butyldimethylsilyl-4-aza-5 ⁇ -androstan-3-one from Example 24D is desilylated as in Example 19C and etherified and cyclopropanated as in Preparation 7D to give the title compound.
  • the compound has the following structural formula:
  • the Grignard solution is stirred an additional 14 hours at room temperature after adding the bromide solution, after which is added a solution of 3 ⁇ -acetoxy-17 ⁇ - tert -butyldimethylsilyloxy-androst-5-en-7-one (40.000 g, 86.821 mmol) prepared in Example 16B or otherwise obtained in THF (500 mL) while maintaining an inert atmosphere. The addition is allowed to occur over 24 hours at room temperature.
  • Example 16D The diastereomer mixture prepared above is oxidized as in Example 16D to give 17 ⁇ - tert -butyldimethylsilyloxy-7 ⁇ -p -tolyl-androsta-4,6-dien-3-one, which is then reduced (hydrogenated) as in Example 16E to give 17 ⁇ - tert -butyldimethylsilyloxy-7 ⁇ - p -tolyl-androst-5-en-3-one (C 5 -olefin).
  • Example 16F The C 5 -olefin is isomerized and desilylated as in Example 16F to give 17 ⁇ -hydroxy-7 ⁇ - p -tolyl-androst-4-en-3-one, which is converted into 17 ⁇ -hydroxy-5-oxo-7 ⁇ - p -tolyl-4-nor-3,5- seco -androstane-3-carboxylic acid as in Example 6A ( seco- acid).
  • the seco-acid is then converted into 17 ⁇ -acetoxy-7 ⁇ - p -tolyl-4-aza-androst-5-en-3-one.
  • 17 ⁇ -Acetoxy-7 ⁇ - p -tolyl-4-aza-androst-5-en-3-one is hydrogenated as in Example 6C to give 17 ⁇ -acetoxy-7 ⁇ - p tolyl-4-aza-5 ⁇ -androstan-3-one, then hydrolyzed as in Preparation 7C to give the title compound.
  • Example 26A 17 ⁇ -Hydroxy-7 ⁇ - p -tolyl-4-aza-5 ⁇ -androstan-3-one prepared in Example 26A is C 17 -oxidized and cycloaminated as in Examples 6D and 6E, respectively, to give the title compound.
  • Androst-4-ene-3,17-dione is oxidized into 5-ozo-4-nor-3,5- seco -androstane-5,17-dione as in Example 6A ( seco -acid).
  • the seco-acid (9.000 g, 31.423 mmol) is slurried with methylammonium chloride (19.5000 g, 288.80 mmol) into acetic acid (75 mL) and heated to reflux under an inert atmosphere. After 3 days, the reaction mixture is allowed to cool to room temperature and diluted with ethyl acetate (EtOAc, 500 mL).
  • the reaction mixture is stirred another 30 minutes and a third charge of sodium methoxide (0.100 g, 1.851 mmol) and another portion of diethyl oxalate (0.30 mL, 2.209 mmol) are added.
  • the reaction solution is allowed to warm to room temperature and is stirred under nitrogen for 16 hours.
  • the solution is then evaporated to dryness and taken up in acetone (50 mL).
  • the acetone solution is transferred to a 100 mL Ace Glass® pressure tube and treated with methyl iodide (3.50 mL, 56.22 mmol).
  • the pressure tube is sealed and heated to 55°C for 22 hours. At the end of this time, the pressure tube is cooled to 0°C and carefully vented.
  • Example 27A 4-Methyl-16 ⁇ -(2-propen-1-yl)-4-aza-androst-5-ene-3,17-dione prepared in Example 27A or otherwise obtained is cycloaminated as in Example 6E to give the title compound.
  • the compound has the following formula:
  • Example 27A 4-Methyl-16 ⁇ -(2-propen-1-yl)-4-aza-androst-5-ene-3,17-dione prepared in Example 27A or otherwise obtained is reduced to give the C 17 -alcohol as in Example 20A, and then etherified and cyclopropanated as in Preparation 7D to obtain the title compound.
  • the reaction mixture is stirred at ambient temperature for 2 hours, then treated with NaI (70.000 g, 467.01 mmol).
  • the reaction solution is stirred for an additional 30 minutes, then treated with a mixture of sodium thiosulfate (Na 2 S 2 O 3 , 95.000 g, 600.85 mmol) in a mixture of water (150 mL) and pyridine (35.0 mL, 432.7 mmol).
  • the resulting solution is stirred at room temperature for another 3 hours.
  • the reaction mixture is then diluted with water (300 mL) and THF is evaporated under reduced pressure. The precipitate which forms is collected by filtration and is recrystallized from ethanol to afford the title compound.
  • 17,17-Ethylenedioxy-androst-5,15(16)-dien-3 ⁇ -ol acetate from Example 28B or otherwise obtained is dissolved in acetone (500 mL) and water (60 mL) and the solution is cooled to 0°C.
  • acetone 500 mL
  • water 60 mL
  • p -toluenesulfonic acid monohydrata 1.000 g, 5.257 mmol
  • the 0° reaction mixture is stirred for 5 hours and then stored at 4° for 16 hours.
  • the chilled reaction solution is diluted with water (300 mL) and acetone is evaporated under reduced pressure.
  • Cuprous chloride (CuCl, 0.7611 g, 7.689 mmol) is slurried in THF (40 mL) under nitrogen and then chilled to -22°C with a dry ice/tetrachloroethylene bath.
  • Ethylmagnesium chloride solution (2.00 M in ether; 22.0 mL, 44.0 mmol) is added to the cold cuprous chloride slurry and the dark solution is stirred for 90 minutes.
  • Example 19C Purification by flash chromatography gives 15 ⁇ -ethyl-3 ⁇ - t -butyldimethylsilyloxy-androst-5-en-17-one, which is deprotected as in Example 19C to give the corresponding 3-alcohol, which is then oxidized as in Example 16D to obtain the title compound, which has the following formula:
  • 15 ⁇ -Ethyl-androst-4-ene-3,17-dione from Example 28D or otherwise obtained is oxidized into 15 ⁇ -ethyl-5,17-dioxo-4-nor-3,5- seco -androstane-3-carboxylic acid ( seco -acid) as in Example 6A, which is then converted into 15 ⁇ -ethyl-4-aza-androst-5-en-3,17-dione as in Example 6B.

Claims (30)

  1. Composé de la formule générale suivante:
    Figure 01420001
    dans laquelle:
    A est O ou NH;
    R1 est H ou un groupe alkyle en C1-4;
    R2 est H, un atome d'halogène, un groupe phénylthio, phénylsulfinyle ou phénylsulfonyle;
    R3 est H, un atome d'halogène, un groupe alkylthio en C1-4, alkylsulfinyle en C1-4 ou alkylsulfonyle en C1-4;
    R4 est H, un groupe alkyle en C1-4 ou alcényle en C2-4;
    R5 est H, un groupe alkyle en C1-4;
    Z est:
    a) un groupe oxo;
    b) (H) (H) ou un atome d'hydrogène en α et un substituant en β choisi dans le groupe constitué par: un groupe alkyle en C1-4, alcényle en C2-4, hydroxy, alcanoyloxy en C1-4, (alcoxy en C1-4)carbonylméthyle, carboxyméthyle, (alcoxy en C1-4)carbonyle, carboxy, alcanoyle en C1-4 et halogène;
       et
    --- signifie la présence éventuelle d'une double liaison
    à condition que:
    a) lorsque R2 est présent et qu'il est différent d'un atome d'hydrogène, une double liaison 1,2 soit présente,
    b) lorsque Z est un groupe oxo, une double liaison 6,7 ne soit pas présente et
    c) lorsque R1 est un groupe CH3 et R2, R3, R4 et R5 sont H et Z est (H) (H) et qu'il n'y a aucune double liaison dans n'importe laquelle des positions 1(2), 5(6) ou 6(7), A ne soit pas NH
    ou un de ses sels pharmaceutiquement acceptables.
  2. Composé selon la revendication 1 de la formule générale suivante:
    Figure 01430001
    dans laquelle
    A est O ou NH;
    R1 est H ou un groupe alkyle en C1-4;
    R2 est H ou un atome d'halogène;
    R3 est H ou un atome d'halogène; et
    Z est (H) (H) ou un atome d'hydrogène en α et un substituant en β choisi dans le groupe constitué par: un groupe alkyle en C1-4, (alcoxy en C1-4)carbonylméthyle et carboxyméthyle
    ou un de ses sels pharmaceutiquement acceptables.
  3. Composé selon la revendication 2 de la formule générale suivante:
    Figure 01430002
    dans laquelle:
    A est O ou NH;
    R1 est H ou un groupe alkyle en C1-4;
    R2 est H ou fluoro
    ou un de ses sels pharmaceutiquement acceptables.
  4. Composé selon la revendication 3 de la formule suivante:
    Figure 01440001
    ou un de ses sels pharmaceutiquement acceptables.
  5. Composé selon la revendication 3 de la formule suivante:
    Figure 01440002
    ou un de ses sels pharmaceutiquement acceptables.
  6. Composé selon la revendication 3 de la formule suivante:
    Figure 01440003
    ou un de ses sels pharmaceutiquement acceptables.
  7. Composé selon la revendication 3 de la formule suivante:
    Figure 01450001
    ou un de ses sels pharmaceutiquement acceptables.
  8. Composé selon la revendication 3 de la formule suivante:
    Figure 01450002
    ou un de ses sels pharmaceutiquement acceptables..
  9. Composé de formule:
    Figure 01450003
    dans laquelle:
    A est O ou NH;
    R1 est H ou un groupe alkyle en C1-4;
    R2 est H, un atome d'halogène, un groupe phénylthio, phénylsulfinyle ou phénylsulfonyle;
    R3 est H, un atome d'halogène, un groupe alkylthio en C1-4, alkylsulfinyle en C1-4 ou alkylsulfonyle en C1-4;
    R4 est H, un groupe alkyle en C1-4 ou alcényle en C2-4;
    R5 est H, un groupe alkyle en C1-4;
    Z est:
    a) un groupe oxo;
    b) (H) (H) ou un atome d'hydrogène en α et un substituant en β choisi dans le groupe constitué par: un groupe alkyle en C1-4, alcényle en C2-4, hydroxy, alcanoyloxy en C1-4, (alcoxy en C1-4)carbonylméthyle, carboxyméthyle, (alcoxy en C1-4)carbonyle, carboxy, alcanoyle en C1-4 et halogène;
       et
    --- signifie la présence éventuelle d'une double liaison
    à condition que:
    a) lorsque R2 est présent et qu'il est différent d'un atome d'hydrogène, une double liaison 1,2 soit présente et
    b) lorsque Z est un groupe oxo, une double liaison 6,7 ne soit pas présente ou un de ses sels pharmaceutiquement acceptables, pour une utilisation en tant que médicament.
  10. Composé selon la revendication 9 de formule:
    Figure 01460001
    dans laquelle:
    A est O ou NH;
    R1 est H ou un groupe alkyle en C1-4;
    R2 est H ou un atome d'halogène;
    R3 est H ou un atome d'halogène; et
    Z est (H) (H) ou un atome d'hydrogène en α et un substituant en β choisi dans le groupe constitué par: un groupe alkyle en C1-4, (alcoxy en C1-4)carbonylméthyle et carboxyméthyle
    ou un de ses sels pharmaceutiquement acceptables, pour une utilisation en tant que médicament.
  11. Composé selon la revendication 9 de formule:
    Figure 01470001
    dans laquelle:
    A est O ou NH;
    R1 est H ou un groupe alkyle en C1-4;
    R2 est H ou fluoro
    ou un de ses sels pharmaceutiquement acceptables, pour une utilisation en tant que médicament.
  12. Utilisation d'un composé selon l'une quelconque des revendications 1 à 11 pour préparer un médicament pour inhiber la C17-20 lyase et la 5α-réductase chez un patient en ayant besoin.
  13. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 et 7 à 11 pour préparer un médicament pour inhiber la C17-20 lyase chez un patient en ayant besoin.
  14. Utilisation selon la revendication 13 dans laquelle le composé a la formule:
    Figure 01470002
  15. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 et 9 à 11 pour préparer un médicament pour inhiber la 5α-réductase chez un patient en ayant besoin.
  16. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 et 9 à 11 pour préparer un médicament pour traiter les troubles androgéno-dépendants chez un patient en ayant besoin.
  17. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 et 9 à 11 pour préparer un médicament pour traiter le syndrome de Stein-Leventhal chez un patient en ayant besoin.
  18. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 et 9 à 11 pour préparer un médicament pour traiter l'hypertrophie de la prostate chez un patient en ayant besoin.
  19. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 et 9 à 11 pour préparer un médicament pour traiter le cancer de la prostate chez un patient en ayant besoin.
  20. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 et 9 à 11 pour préparer un médicament pour traiter une maladie médiée par la DHT chez un patient en ayant besoin.
  21. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 et 9 à 11 pour préparer un médicament pour traiter l'acné chez un patient en ayant besoin.
  22. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 et 9 à 11 pour préparer un médicament pour traiter un trouble médié par les estrogènes ou dépendant des estrogènes chez un patient en ayant besoin.
  23. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 et 9 à 1 pour préparer un médicament pour traiter le cancer du sein chez un patient en ayant besoin.
  24. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 et 9 à 11 pour préparer un médicament pour inhiber la C17-hydroxylase chez un patient en ayant besoin.
  25. Utilisation d'un composé selon l'une quelconque des revendications 1 à 5 et 9 à 11 pour préparer un médicament pour traiter le syndrome de Cushing chez un patient en ayant besoin.
  26. Composition pharmaceutique comprenant un composé selon l'une quelconque des revendications 1 à 11 en mélange avec un excipient pharmaceutiquement acceptable.
  27. Produit contenant un composé selon l'une quelconque des revendications 1 à 11 et un antagoniste des récepteurs des androgènes en tant que préparation pour une thérapie par association pour le traitement des troubles dépendant des androgènes.
  28. Produit selon la revendication 27, dans lequel l'antagoniste des récepteurs des androgènes est le flutamide.
  29. Produit contenant un composé selon l'une quelconque des revendications 1 à 11 et un antagoniste des récepteurs des androgènes en tant que préparation pour une thérapie par association pour le traitement du cancer de la prostate.
  30. Produit selon la revendication 29, dans lequel l'antagoniste des récepteurs des androgènes est le flutamide.
EP97901995A 1996-02-14 1997-01-09 17-beta-cyclopropyl(amino/oxy) 4-aza steroides utilises en qualites d'inhibiteurs de 5-alpha-reductase et de c17-20-lyase de testosterone Expired - Lifetime EP0880540B1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US601278 1995-07-20
US60127896A 1996-02-14 1996-02-14
PCT/US1997/000469 WO1997030069A1 (fr) 1996-02-14 1997-01-09 17-beta-cyclopropyl(amino/oxy) 4-aza steroides utilises en qualites d'inhibiteurs de 5-alpha-reductase et de c17-20-lyase de testosterone

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EP0880540A1 EP0880540A1 (fr) 1998-12-02
EP0880540B1 true EP0880540B1 (fr) 2002-06-12

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JP (1) JP2000505444A (fr)
KR (1) KR19990082543A (fr)
CN (1) CN1211256A (fr)
AT (1) ATE219100T1 (fr)
AU (1) AU710208B2 (fr)
BR (1) BR9708301A (fr)
CA (1) CA2244823A1 (fr)
DE (1) DE69713285T2 (fr)
DK (1) DK0880540T3 (fr)
ES (1) ES2178750T3 (fr)
HU (1) HUP9900955A3 (fr)
IL (1) IL125575A0 (fr)
NO (1) NO983724L (fr)
NZ (1) NZ327041A (fr)
PT (1) PT880540E (fr)
WO (1) WO1997030069A1 (fr)

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RU2481107C2 (ru) * 2007-10-29 2013-05-10 Такеда Фармасьютикал Компани Лимитед Средство для профилактики или лечения рака

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US6187925B1 (en) 1997-12-23 2001-02-13 Merck & Co., Inc. Intermediates and process for the synthesis of azasteroids
US7005428B1 (en) 1998-06-11 2006-02-28 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
US6465445B1 (en) * 1998-06-11 2002-10-15 Endorecherche, Inc. Medical uses of a selective estrogen receptor modulator in combination with sex steroid precursors
AU2002221080A1 (en) * 2000-12-08 2002-06-18 Masami Kusaka Substituted thiazole derivatives bearing 3-pyridyl groups, process for preparingthe same and use thereof
JP4832303B2 (ja) 2003-05-07 2011-12-07 メルク・シャープ・エンド・ドーム・コーポレイション アンドロゲン受容体モジュレータおよびこれらの使用
JP2012506906A (ja) * 2008-10-28 2012-03-22 バイオマリン ファーマシューティカル インコーポレイテッド デカヒドロ−１ｈ−インデノキノリンおよびデカヒドロ−３ｈ−シクロペンタフェナントリジノンｃｙｐ１７インヒビター
WO2011088160A2 (fr) * 2010-01-15 2011-07-21 Biomarin Pharmaceutical Inc. Nouveaux inhibiteurs de cyp17
GB201102913D0 (en) 2011-02-18 2011-04-06 Univ Birmingham Novel therapeutic
CN109438549B (zh) * 2018-12-13 2022-01-04 湖北葛店人福药业有限责任公司 一种制备N-叔丁基-3-氧代-4-氮杂-5α-雄甾-17β-甲酰胺的方法

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US5264427A (en) * 1992-01-29 1993-11-23 Research Corporation Technologies, Inc. 20-substituted pregnene derivatives and their use as androgen synthesis inhibitors
EP0641211A1 (fr) * 1992-05-21 1995-03-08 Endorecherche Inc. INHIBITEURS D'ACTIVITE DE LA TESTOSTERONE 5$g(a)-REDUCTASE
US5486511A (en) * 1993-05-25 1996-01-23 Merrell Dow Pharmaceuticals Inc. 4-amino-17β-(cyclopropyloxy)androst-4-en-3-one, 4-amino-17β-(cyclopropylamino)androst-4-en-3-one and related compounds as C17-20 lyase and 5α-reductase

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2481107C2 (ru) * 2007-10-29 2013-05-10 Такеда Фармасьютикал Компани Лимитед Средство для профилактики или лечения рака

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NZ327041A (en) 1999-11-29
AU710208B2 (en) 1999-09-16
WO1997030069A1 (fr) 1997-08-21
ES2178750T3 (es) 2003-01-01
DE69713285D1 (en) 2002-07-18
CA2244823A1 (fr) 1997-08-21
JP2000505444A (ja) 2000-05-09
PT880540E (pt) 2002-10-31
DE69713285T2 (de) 2003-01-02
HUP9900955A2 (hu) 1999-07-28
IL125575A0 (en) 1999-03-12
DK0880540T3 (da) 2002-10-07
BR9708301A (pt) 1999-08-03
EP0880540A1 (fr) 1998-12-02
AU1576797A (en) 1997-09-02
NO983724L (no) 1998-10-13
CN1211256A (zh) 1999-03-17
KR19990082543A (ko) 1999-11-25
NO983724D0 (no) 1998-08-13
ATE219100T1 (de) 2002-06-15
HUP9900955A3 (en) 2000-06-28

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